3.0 Lamotrigine, bioequivalence, and interchangeabilty
Prior to the Sole Supply Decision, PHARMAC funded three brands of lamotrigine: Lamictal (supplied by GSK), Arrow-Lamotrigine (supplied by Teva), and Logem (supplied by Mylan).
Lamictal is the ‘innovator’ brand. It was being taken by 62% of patients taking lamotrigine. Arrow-Lamotrigine was being taken by 26% of patients; and Logem was being taken by 12% of patients.
Medsafe approved Logem in September 2016. Logem was first listed on the Pharmaceutical Schedule on 1 June 2018.
The issues relating to brand changes in medications are not new and have been extensively discussed in New Zealand and internationally. The scientific discipline and clinical specialty that involves all aspects of the relationship between drugs and humans, and the quality use of medicines, is clinical pharmacology. The brief overview that follows in this section is taken from A/Prof Doogue’s advice, which is set out in full as Appendix 2.
The concept of bioequivalence is important to understanding the Sole Supply Decision. A/Prof Doogue refers to bioequivalence as “taking one brand of a medicine gives the same amount of drug in the body as taking another”. Two brands of the same medicine are bioequivalent when the same dose gives the same concentration of medicine in people taking the medicine. If the two brands are bioequivalent, then “the same dose is expected to produce the same clinical effect regardless of which brand is used”.
Any new brand must demonstrate bioequivalence to the existing (reference) brand. The reference brand is usually the ‘originator’ (or innovator) brand. Medsafe is the regulator in New Zealand responsible for establishing that generic medicines are bioequivalent to the originator brand.
Interchangeability means that two brands are expected to produce the same results when consistently used. Interchangeability is regulated by Medsafe.
Substitutability means that two brands can be switched. Substitution is undertaken at pharmacies. A/Prof Doogue advises that usual practice in New Zealand is for pharmacies to continue the same brand where possible, especially for narrow therapeutic index drugs; but that brand substitution is permitted. Prior to moving to Logem as the sole brand, substitution between the three funded brands of lamotrigine could occur at the pharmacy level (if, for example, the pharmacy had no stock of one brand).
The potential risks associated with interchangeability and substitution include patient confusion due to changes in packaging or tablet appearance, and patients having pre-existing preferences for brands which can affect confidence and adherence to regimens, and may result in placebo/nocebo effects (i.e. some of the effects of the medicine might be due to non-pharmacological factors which are affected by expectations and beliefs). These risks can be mitigated, but not eliminated, by patient counselling at the time of brand switching.
In the case of lamotrigine, bioequivalence between Logem and Lamictal (the originator/innovator brand) was established prior to Logem being distributed for use in New Zealand. In December 2019, after reports of issues after switching brands were raised, Medsafe reaffirmed the bioequivalence between Logem and Lamictal. A/Prof Doogue advises that because lamotrigine brand changes have previously been associated with uncertainty, differences (or not) between brands of lamotrigine have been more thoroughly studied than for most medicines.
A/Prof Doogue refers to the ‘social risks’ of brand change. Specifically, he refers to:
Change in adherence, confusion, and consequently not taking the medicine in the same way causing a difference in drug effects;
A change in placebo/nocebo effect; and
Events occurring regardless of the brand change; and that any event occurring soon after a change may be attributed to the change.
A/Prof Doogue advises that, for reasons not well understood, patients with epilepsy report issues with brand changes more than are reported with brand changes for most other conditions. A characteristic of epilepsy is that seizures are dramatic, intermittent events that fluctuate in frequency. Changes to epilepsy control occur, and are not always easy to explain.